Rigorous scoping review of randomized trials in pediatric critical care highlights need for a rigorous rethink

The randomized controlled trial (RCT) remains the highest-ranked study design when grading recommendations for clinical practice. In the previous issue of Critical Care, Duffett and colleagues published a scoping review of RCTs in pediatric critical care medicine and identified some serious gaps in the body of research underlying the field. Relatively few published RCTs were identified, and they were mostly small and potentially susceptible to bias. High patient heterogeneity, relatively low prevalence of specific disorders such as acute respiratory distress syndrome or septic shock, along with relatively low mortality rates, all make it difficult to improve this situation without the collaboration of pediatric critical care research networks internationally. Designing a robust RCT that can impact clinical practice has always been challenging. First, one must assess current clinical practice and disease prevalence, refine definitions and measurements, and pilot-test the intervention to be studied. The first step, however, is to rigorously assess what has already been done. This step will be facilitated by the now available, innovative, online, searchable repository of RCTs in pediatric critical care on the Evidence in Pediatric Critical Care website

Pediatric sepsis: Important considerations for diagnosing and managing severe infections in infants, children, and adolescents

Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments

Effect of lung compliance and endotracheal tube leakage on measurement of tidal volume

INTRODUCTION: The objective of this laboratory study was to measure the effect of decreased lung compliance and endotracheal tube (ETT) leakage on measured exhaled tidal volume at the airway and at the ventilator, in a research study with a test lung. METHODS: The subjects were infant, adult and pediatric test lungs. In the test lung model, lung compliances were set to normal and to levels seen in acute respiratory distress syndrome. Set tidal volume was 6 ml/kg across a range of simulated weights and ETT sizes. Data were recorded from both the ventilator light-emitting diode display and the CO(2)SMO Plus monitor display by a single observer. Effective tidal volume was calculated from a standard equation. RESULTS: In all test lung models, exhaled tidal volume measured at the airway decreased markedly with decreasing lung compliance, but measurement at the ventilator showed minimal change. In the absence of a simulated ETT leak, calculation of the effective tidal volume led to measurements very similar to exhaled tidal volume measured at the ETT. With a simulated ETT tube leak, the effective tidal volume markedly overestimated tidal volume measured at the airway. CONCLUSION: Previous investigators have emphasized the need to measure tidal volume at the ETT for all children. When ETT leakage is minimal, it seems from our simulated lung models that calculation of effective tidal volume would give similar readings to tidal volume measured at the airway, even in small patients. Future studies of tidal volume measurement accuracy in mechanically ventilated children should control for the degree of ETT leakage

Pulmonary Specific Ancillary Treatment for Pediatric Acute Respiratory Distress Syndrome:From the Second Pediatric Acute Lung Injury Consensus Conference

OBJECTIVES: We conducted an updated review of the literature on pulmonary-specific ancillary therapies for pediatric acute respiratory distress syndrome (PARDS) to provide an update to the Pediatric Acute Lung Injury Consensus Conference recommendations and statements about clinical practice and research. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: Searches were limited to children, PARDS or hypoxic respiratory failure and overlap with pulmonary-specific ancillary therapies DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data collection form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-six studies were identified for full-text extraction. Four clinical recommendations were generated, related to use of inhaled nitric oxide, surfactant, prone positioning, and corticosteroids. Two good practice statements were generated on the use of routine endotracheal suctioning and installation of isotonic saline prior to endotracheal suctioning. Three research statements were generated related to: the use of open versus closed suctioning, specific methods of airway clearance, and various other ancillary therapies. CONCLUSIONS: The evidence to support or refute any of the specific ancillary therapies in children with PARDS remains low. Further investigation, including a focus on specific subpopulations, is needed to better understand the role, if any, of these various ancillary therapies in PARDS.</p

Association between length of storage of red blood cell units and outcome of critically ill children: a prospective observational study

INTRODUCTION: Transfusion is a common treatment in pediatric intensive care units (PICUs). Studies in adults suggest that prolonged storage of red blood cell units is associated with worse clinical outcome. No prospective study has been conducted in children. Our objectives were to assess the clinical impact of the length of storage of red blood cell units on clinical outcome of critically ill children. METHODS: Prospective, observational study conducted in 30 North American centers, in consecutive patients aged \u3c18 years with a stay\u3eor= 48 hours in a PICU. The primary outcome measure was the incidence of multiple organ dysfunction syndrome after transfusion. The secondary outcomes were 28-day mortality and PICU length of stay. Odds ratios were adjusted for gender, age, number of organ dysfunctions at admission, total number of transfusions, and total dose of transfusion, using a multiple logistic regression model. RESULTS: The median length of storage was 14 days in 296 patients with documented length of storage. For patients receiving blood stored \u3eor= 14 days, the adjusted odds ratio for an increased incidence of multiple organ dysfunction syndrome was 1.87 (95% CI 1.04;3.27, P = 0.03). There was also a significant difference in the total PICU length of stay (adjusted median difference +3.7 days, P \u3c 0.001) and no significant change in mortality. CONCLUSIONS: In critically ill children, transfusion of red blood cell units stored for \u3eor= 14 days is independently associated with an increased occurrence of multiple organ dysfunction syndrome and prolonged PICU stay

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q&lt;0.05).ResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome

Systemic and Lower Respiratory Tract Immunity to SARS-CoV-2 Omicron and Variants in Pediatric Severe COVID-19 and Mis-C

Mucosal immunity plays an important role in the control of viral respiratory infections like SARS-CoV-2. While systemic immune responses against the SARS-2-CoV-2 have been studied in children, there is no information on mucosal antibody response, especially in the lower respiratory tract of children coronavirus disease 2019 (COVID-19) and post-infectious multisystem inflammatory syndrome in children (MIS-C) against emerging SARS-CoV-2 variants. Therefore, we evaluated neutralizing antibody responses in paired plasma and endotracheal aspirates of pediatric severe, acute COVID-19 or MIS-C patients against SARS-CoV-2 WA1/2020, as well as against variants of concern (VOCs). Neutralizing antibody responses against the SARS-CoV-2 WA1/2020 strain in pediatric plasma were 2-fold or 35-fold higher compared with the matched endotracheal aspirate in COVID-19 or MIS-C patients, respectively. In contrast to plasma, neutralizing antibody responses against the VOCs and variants of interest (VOIs) in endotracheal aspirates were lower, with only one endotracheal aspirate demonstrating neutralizing titers against the Iota, Kappa, Beta, Gamma, and Omicron variants. In conclusion, our findings suggest that children and adolescents with severe COVID-19 or MIS-C have weak mucosal neutralizing antibodies in the trachea against circulating SARS-CoV-2 Omicron and other VOCs, which may have implications for recovery and for re-infection with emerging SARS-CoV-2 variants

Evaluation of Mannose Binding Lectin Gene Variants in Pediatric Influenza Virus-Related Critical Illness

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections.Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450Gly54Asp(“B”), rs1800451Gly57Glu(“C”), rs5030737Arg52Cys(“D”) in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes (“B/B,” “C/C”) to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity.Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p &lt; 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002).Conclusions:MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death

Exuberant fibroblast activity compromises lung function via ADAMTS4

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections